Illudin analogs useful as antitumor agents
Abstract
The present invention provides illudin analogs of the general formula (I): where R 1 is (CH 2 ) n —X—Y or H; n is 0 to 4; X is O or S or N or absent; and Y is an optionally substituted (C 1 -C 8 )alkyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 4 )alkyl or cyclo(C 3 -C 6 )alkyl optionally comprising one or more heteroatoms; a monosaccharide, an amino acid residue, or H when n is 2-4; R 2 is absent; or R 1 and R 2 together comprise a 5-7 membered cyclic ring; R 3 is (C 1 -C 4 )alkyl or H; R 4 is H, SCH 2 CO 2 (C 1 -C 4 )alkyl, O—(C 5 -C 12 )aryl or —S—(C 5 -C 12 )aryl; R 5 is H, OH or absent; R 6 is (C 1 -C 4 )alkyl or absent; R 7 is OH or OSi((C 1 -C 4 )alkyl) 3 ; or R 6 and R 7 together are ethylenedioxy; R 8 is optionally substituted (C 1 -C 4 )alkyl; and the bonds represented by ----- are individually present or absent. The invention further provides dimers comprising analogs of formula (I).
Claims
exact text as granted — not AI-modified1. A compound of formula I:
wherein R 1 is (CH 2 ) n —X—Y,
where n is 0 to 4;
X is O or S or NH, and
Y is (C 1 -C 8 )alkyl optionally substituted with 1-2 OH or 1-2 halo; or —(C 1 -C 8 )alkyl-O—(C 1 -C 8 )alkyl R 3 is H or (C 1 -C 4 )alkyl;
R 4 is SCH 2 CO 2 (C 1 -C 4 )alkyl, —S—(C 6 -C 10 )aryl optionally substituted with halo, OH or (C 1 -C 4 )alkyl, or H;
R 5 is H, OH or absent;
R 6 is (C 1 -C 4 )alkyl;
R 7 is OH or —O(Si((C 1 -C 4 )alkyl) 3 ; or
R 6 and R 7 together are ethylenedioxy;
R 8 is (C 1 -C 4 )alkyl optionally comprising OH or halo;
the bond represented by ----- is present or absent; or
a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein the bond represented by ---- is present, R 3 is CH 3 , R 4 is H, R 5 is absent, R 6 is CH 3 , R 7 is OH, and R 8 is CH 3 .
3. The compound of claim 2 wherein n is 1, X is O, and Y is (C 1 -C 8 )alkyl optionally substituted with 1 to 2 OH, or 1 to 2 halo.
4. The compound of claim 3 wherein Y is (C 1 -C 8 )alkyl.
5. The compound of claim 4 wherein the compound of formula I is:
6. A compound of the formula I:
wherein
R 1 is (CH 2 ) n —Y,
where n is 0 to 4;
Y is CHO, NH 2 , COOH, —(C 2 -C 4 )alkenyl-CHO, —CH(O(C 1 -C 4 )alkyl) 2 , cyclo(C 3 -C 6 )alkyl, or 5-membered heteroaryl comprising one to three heteroatoms selected from N, S, or non-peroxide O, where the cycloalkyl or heteroaryl is optionally substituted with 1 or 2 (C 1 -C 4 )alkyl, CHO, OH, or halo groups;
R 3 is H or (C 1 -C 4 )alkyl;
R 4 is H; SCH 2 CO 2 (C 1 -C 4 )alkyl; or —O—(C 5 -C 12 )aryl or —S—(C 5 -C 12 )aryl optionally substituted with halo, OH or (C 1 -C 4 )alkyl;
R 5 is H, OH, or absent;
R 6 is (C 1 -C 4 )alkyl or H;
R 7 is OH or —O(Si((C 1 -C 4 )alkyl) 3 ; or
R 6 and R 7 together are ethylenedioxy;
R 8 is (C 1 -C 4 )alkyl optionally comprising OH or halo;
the bond represented by --- is present or absent; or
a pharmaceutically acceptable salt thereof.
7. The compound of claim 6 wherein the bond represented by ---- is present, R 3 is CH 3 , R 4 is H, R 5 is absent, R 6 is CH 3 , R 7 is OH, and R 8 is CH 3 .
8. The compound of claim 7 wherein n is 0 or 1.
9. The compound of claim 8 wherein n is 0 and Y is —(C 2 -C 4 alkenyl-CHO.
10. The compound of claim 6 wherein the compound of formula I is:
11. The compound of claim 8 wherein n is 1 and Y is a 5-membered heteroaryl comprising 1 or 2 nitrogen atoms.
12. The compound of claim 11 wherein the 5-membered heteroaryl is an imidazole.
13. The compound of claim 12 wherein the compound of formula I is a pharmaceutically acceptable salt of:
14. A compound of the formula I:
wherein
R 1 is (CH 2 ) n —Y,
where n is 2 to 4;
Y is CHO, NO 2 , NH 2 , COOH, —(C 2 -C 4 )alkenyl-CHO, —CH(O(C 1 -C 4 )alkyl) 2 , cyclo(C 3 -C 6 )alkyl, 5-membered heteroaryl comprising one to three heteroatoms selected from N, or non-peroxide O, where the cycloalkyl or heteroaryl is optionally substituted with 1 or 2 (C 1 -C 4 )alkyl, CHO, OH, or halo groups; or H;
R 3 is H or (C 1 -C 4 )alkyl;
R 4 is H; SCH 2 CO 2 (C 1 -C 4 )alkyl; or —O—(C 5 -C 12 )aryl or —S—(C 5 -C 12 )aryl optionally substituted with halo, OH or (C 1 -C 4 )alkyl;
R 5 is H, OH, or absent;
R 6 is (C 1 -C 4 )alkyl or H;
R 7 is OH or —O(Si((C 1 -C 4 )alkyl) 3 ; or
R 6 and R 7 together are ethylenedioxy;
R 8 is (C 1 -C 4 )alkyl optionally comprising OH or halo;
the bond represented by --- is present or absent; or
a pharmaceutically acceptable salt thereof.
15. The compound of claim 14 wherein the bond represented by ---- is present, R 3 is CH 3 , R 4 is H, R 5 is absent, R 6 is CH 3 , and R 7 is OH.
16. The compound of claim 15 wherein n is 2 or 3.
17. The compound of claim 16 wherein n is 2 and Y is COOH.
18. The compound of claim 17 wherein the compound of formula I is:
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 16 wherein n is 3 and Y is NH 2 .
20. The compound of claim 19 wherein the compound of formula I is:
or a pharmaceutically acceptable salt thereof.Join the waitlist — get patent alerts
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